Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 87

Alzheimer’s disease has been identified as a protein-misfolding proteopathy. In 1991, the amyloid hypothesis was proposed, based on the discovery that senile plaques were composed of 39 to 43 amino acid peptides called beta amyloid or A-beta (Aβ) peptides, which were proteolytic fragments of a larger precursor protein, the APP (amyloid precursor protein). The enzymes involved in proteolysis were found to be gamma secretase and BACE-1. Beta amyloid deposits outside neurons to form dense senile plaques, thought by scientists to be the fundamental cause of disease.

The location of the gene for APP on chromosome 21 and the strong association of AD with Down syndrome (trisomy 21) as well as the presence of mutations in the gene for presenelin (proteins involved in processing of APP) in patients with AD support the amyloid hypothesis. It is further noted that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise, indicating Aβ deposition precedes clinical AD. Mature amyloid plaques are suspected to be neurotoxic, and it is also proposed that normal mitochondrial function is disrupted in brain neurons by selective Aβ build-up, leading to decreased glucose utilization in neurons, formation of reactive oxygen species, calcium influx, and apoptosis even before formation of fibrils and plaques by unknown mechanisms. The primary mechanisms remain unclear.